EP0123504A2 - Komplexe von Technetium-99m mit Alkylenaminoximen - Google Patents
Komplexe von Technetium-99m mit Alkylenaminoximen Download PDFInfo
- Publication number
- EP0123504A2 EP0123504A2 EP84302615A EP84302615A EP0123504A2 EP 0123504 A2 EP0123504 A2 EP 0123504A2 EP 84302615 A EP84302615 A EP 84302615A EP 84302615 A EP84302615 A EP 84302615A EP 0123504 A2 EP0123504 A2 EP 0123504A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- complex
- pnao
- technetium
- complexes
- brain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- -1 alkylene amine oximes Chemical class 0.000 title claims abstract description 23
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 title claims abstract description 22
- 229940056501 technetium 99m Drugs 0.000 title claims abstract description 13
- 210000004556 brain Anatomy 0.000 claims abstract description 33
- 238000003384 imaging method Methods 0.000 claims abstract description 27
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 14
- 230000008499 blood brain barrier function Effects 0.000 claims abstract description 11
- 210000001218 blood-brain barrier Anatomy 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 8
- 238000007911 parenteral administration Methods 0.000 claims abstract description 4
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 3
- 238000006798 ring closing metathesis reaction Methods 0.000 claims abstract description 3
- 239000003446 ligand Substances 0.000 claims description 54
- 210000004072 lung Anatomy 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 claims description 14
- 229910052713 technetium Inorganic materials 0.000 claims description 13
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 230000002107 myocardial effect Effects 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 238000001727 in vivo Methods 0.000 claims description 9
- 230000000536 complexating effect Effects 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 150000001412 amines Chemical group 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 239000012528 membrane Substances 0.000 claims description 5
- 230000000717 retained effect Effects 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 230000001413 cellular effect Effects 0.000 claims description 3
- 150000003335 secondary amines Chemical class 0.000 claims description 3
- 125000006539 C12 alkyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 150000002632 lipids Chemical class 0.000 claims description 2
- 238000005192 partition Methods 0.000 claims description 2
- 150000003140 primary amides Chemical class 0.000 claims description 2
- 150000003334 secondary amides Chemical class 0.000 claims description 2
- 150000003511 tertiary amides Chemical class 0.000 claims description 2
- 229940127043 diagnostic radiopharmaceutical Drugs 0.000 claims 1
- 230000000149 penetrating effect Effects 0.000 claims 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 abstract description 2
- 239000005977 Ethylene Substances 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- 239000000243 solution Substances 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 150000001875 compounds Chemical class 0.000 description 27
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- 238000002360 preparation method Methods 0.000 description 23
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000523 sample Substances 0.000 description 18
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- 238000006243 chemical reaction Methods 0.000 description 15
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical class NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 12
- 239000013522 chelant Substances 0.000 description 12
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- 150000003839 salts Chemical class 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
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- 238000005481 NMR spectroscopy Methods 0.000 description 11
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- UXOLDCOJRAMLTQ-UTCJRWHESA-N ethyl (2z)-2-chloro-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(\Cl)=N\O UXOLDCOJRAMLTQ-UTCJRWHESA-N 0.000 description 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- 229940121896 radiopharmaceutical Drugs 0.000 description 9
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- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 8
- CHXRIVJFJWPWMR-UHFFFAOYSA-N 2-chloro-2-methyl-3-nitrosobutane Chemical compound O=NC(C)C(C)(C)Cl CHXRIVJFJWPWMR-UHFFFAOYSA-N 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
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- 230000009467 reduction Effects 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
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- 229910052708 sodium Inorganic materials 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 230000017531 blood circulation Effects 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
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- 229920000768 polyamine Chemical group 0.000 description 5
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- YXTDAZMTQFUZHK-ZVGUSBNCSA-L (2r,3r)-2,3-dihydroxybutanedioate;tin(2+) Chemical compound [Sn+2].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O YXTDAZMTQFUZHK-ZVGUSBNCSA-L 0.000 description 4
- LNHIRAPPSXFBJT-UHFFFAOYSA-N 2-methylheptane-1,1-diamine Chemical compound CCCCCC(C)C(N)N LNHIRAPPSXFBJT-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 150000003973 alkyl amines Chemical group 0.000 description 4
- 210000005013 brain tissue Anatomy 0.000 description 4
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- 210000003374 extravascular lung water Anatomy 0.000 description 4
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- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 229940007163 stannous tartrate Drugs 0.000 description 4
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- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- NHRZNVKSDVHXOA-IEOVAKBOSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;technetium-99 Chemical compound [99Tc].OC(=O)CC(O)(C(O)=O)CC(O)=O NHRZNVKSDVHXOA-IEOVAKBOSA-N 0.000 description 3
- FJCWRDBHQRKJGJ-UHFFFAOYSA-N 2-morpholin-4-ylpropane-1,3-diamine Chemical compound NCC(CN)N1CCOCC1 FJCWRDBHQRKJGJ-UHFFFAOYSA-N 0.000 description 3
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 3
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- ZOKXTWBITQBERF-AKLPVKDBSA-N Molybdenum Mo-99 Chemical compound [99Mo] ZOKXTWBITQBERF-AKLPVKDBSA-N 0.000 description 3
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- HAICTRTYRLQQRS-UHFFFAOYSA-N 18-[(2-methyl-3-oxobutan-2-yl)amino]-17-[[(2-methyl-3-oxobutan-2-yl)amino]methyl]octadecanoic acid Chemical compound CC(=O)C(C)(C)NCC(CNC(C)(C)C(C)=O)CCCCCCCCCCCCCCCC(O)=O HAICTRTYRLQQRS-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/15—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen containing halogen
- C07C53/19—Acids containing three or more carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Definitions
- Tc-99m Technetium-99m
- This invention relates to complexes of technetium, e.g. technetium-99m complexes useful as diagnostic pharmaceuticals, and in particular to complexes which are capable of crossing the blood-brain barrier and being retained in the brain for a time to permit diagnosis.
- technetium e.g. technetium-99m complexes useful as diagnostic pharmaceuticals
- complexes which are capable of crossing the blood-brain barrier and being retained in the brain for a time to permit diagnosis.
- Tc-99m is obtained from a technetium generator as pertechnetate ion TcO , with technetium in the 7+ valency, generally in saline solution. Since pertechnetate does not readily form complexes, a usual technique is to mix the pertechnetate with a suitable ligand under reducing conditions, whereby the technetium is reduced to a lower valency, generally 3+, 4+ or 5+ in which it forms the desired complex. A problem is that these complexes almost always carry an overall charge; all Tc-99m complexes so far approved by the FDA for routine use in nuclear medicine in USA have overall positive or negative charges. It is known that charged species will not readily pass through the blood-brain barrier (BBB), and so cannot easily be introduced into the brain.
- BBB blood-brain barrier
- the first is best exemplified by Xe-133, an inert noble gas, that passively diffuses across the BBB and clears the tissue at a rate proportional to the blood flow through that tissue.
- the pattern of rCBF is determined by following the rate of Xe-133 clearance as a function of time at different sites of the brain using either a specialized Single Photon Emission Computed Tomographic (SPECT) instrument or a commercial multidetector system.
- SPECT Single Photon Emission Computed Tomographic
- the second class of compounds include those that passively diffuse across the BBB (with a high extraction efficiency) into the brain and become trapped in the brain tissue.
- the trapping allows time for determination of rCBF patterns by more conventional SPECT imaging devices.
- the two most widely used single photon brain perfusion agents of this latter type are: I-123-N,N,N'-trimethyl-N'-(2-OH-3-methyl-5-iodobenzyl)-1,3-propanediamine,(I-123-HIPDM) and 1-123-Iodoamphetamine, (I-123-IMP). Because Tc-99m has superior imaging properties and is more readily available and less expensive, any new Tc-99m labelled compounds with similar or even better capabilities for brain uptake (and/or washout) as Xe-133, I-123-IMP or I-123-HIPDM would find widespread clinical applicability
- I-123-iodoantipyrene is a hydrophobic compound that distributes following injection throughout the lung water and has been used to assess extravascular lung water (EVLW) in normal and disease states. This agent passively diffuses into the lung parenchyma and is washed out by pulmonary blood flow. Lung imaging has also been performed using 1-123-IMP. I-123-IMP is taken up by lung tissue and slowly released, presumably due to its binding to intracellular low specificity, - high capacity endothelial amine receptors.
- Tc-99m agents that exhibit properties similar to 1-123-iodoantipyrene would have value for measuring regional EVLW imaging (particularly in patients with the acute respiratory distress syndrome).
- a Tc-99m-compound that binds to amine receptors in the lung would be useful for performing metabolic lung imaging.
- Imaging of heart muscle in patients with myocardial damage using fatty acids or fatty acid analogues labelled with positron emitters or 1-123 has shown promise as a diagnostic tool. As indicated earlier, the high cost of producing compounds labelled with positron emitters precludes their widespread availability in the foreseeable future.
- fatty acid oxidation i.e., beta-oxidation
- free fatty acid uptake is decreased.
- Regional fatty acid metabolism could be measured by determining the rate of clearance of the labelled fatty acid from the myocardium.
- a fatty acid analogue that enters the metabolic pathway, undergoes partial metabolism, and whose radioactive label is trapped within the myocardium would also reflect regional metabolic activity (i.e., similar to 18-F-fluorodeoxyglucose for brain metabolic images.
- Fatty acid analogues labelled in various manners with 1-123 are taken up by normal heart muscle and depending upon the structure of the specific compound will either clear rapidly following intracellular beta-oxidation (similar to C-11 labelled fatty acids) or can be structurally modified so they will be trapped by the myocardial tissue.
- 1-123 can be attached directly to the omega-end (i.e., the end opposite the carboxylic acid group) of the alkyl chain or attached to the omega-end of the alkyl chain by means of a I-123-phenyl group. Both types of derivatives have been successfully used as myocardial imaging agents.
- Tc-99m-complexes At least three neutral Tc-99m-complexes have been prepared and reported. See, Burns, et al., J.Nucl. Med., 20, 641, 1979; Kramer, et. al., J. Labelled Compounds and Radiopharmaceuticals, 19, 1598-1599, 1982; Yoko y ama, et al.,J. Nucl. Med., 17, 816-19 (1976). None of these Tc-99m complexes have been established for routine diagnostic use.
- Tc-99m complexes that employ only N-atoms for chelation of Tc-99m have been shown to readily form complexes in aqueous media.
- Tetraaza ligands and in particular macrocyclic tetraaza ligands form very stable Tc-99m complexes.
- Troutner, et al., J. Nucl. Med., 21, 443-448 (1980) which describes the complexing of Tc-99m with the macrocyclic tetraaza ligand, cyclam.
- the only published study showing full characterization of such a macrocyclic ligand complex of Tc was published in 1981 by Zuckman, et al., Inorg. Chem., 20, 2386-2389.
- the complex with cyclam (1,4,8,11-tetraazacyclotetradecane) under reducing conditions was shown to produce a Tc0 2 +1 core, and a resulting complex had a charge of +1.
- PnAO propylene amine oxime
- EnAO ethylene amine oxime
- This invention is based in part on the discovery that technetium-99m can be complexed (by reduction of Tc-99m-pertechnetate in aqueous media) to propyleneamine oxime, to produce a stable lipophilic complex.
- This complex and derivatives will make useful diagnostic imaging agents. This appears to be a general complexation reaction with this type of amine oxime ligand since another form of the basic tetradentate amine oxime ligand, ethyleneamine oxime (EnAO) also forms a neutral-hydrophobic Tc-99m chelate in aqueous solution.
- the complexes have a zero net charge and are easily derivatizable.
- Tc-99m EnAO and PnAO are capable of crossing the blood-brain-barrier, passing through cell walls and being taken up efficiently by lung tissue, thereby extending their range of usefulness as radiopharmaceuticals. Further, the complexes are sufficiently stable, even in the presence of oxygen, to permit their preparation, storage and parenteral administration for imaging.
- the macrocyclic PnAO ring is closed during the formation of the complex by an 0---H---0 bond which serves to complete the ring and control the charge on the complex.
- Tc-99 PnA0 has been determined to be as shown in formula (3) below, in which R 1 , R and R 5 are methyl and R 2 and R 3 are hydrogen. It is expected that the structures of Tc-99 EnAO, of analogues of Tc-99 PnAO and of Tc-99 EnAO, and of the corresponding Tc-99m complexes are essentially as shown in formulae (1) and (2).
- the invention provides a complex of technetium-99m of the kind described and including the structure where n is 2 or 3.
- the technetium core is in the form of Tc0 3+ .
- the statement that the technetium-99m complex of this invention has a core with zero net charge needs some explanation.
- the core of the complex for example as shown in (1) above, has no overall charge, in contrast to other similar Tc-99m complexes. But the attachment of charged or ionizable groups to the carbon atoms shown will result in the complex as a whole having a non-zero charge, at least under some conditions.
- Such complexes, having non-zero overall charge by virtue of charged or ionizable groups attached to the core are of considerable interest for localizing in particular regions of the body, and are included within the scope of this invention.
- the term "zero net charge” thus refers to the macrocyclic core structure and ignores possible charged or ionizable substituent groups.
- complexes of technetium-99m can be designed for specific purposes by attaching suitable groups to any or all of the carbon atoms shown in (1). Such designing of molecules is standard practice in research laboratories nowadays. The attachment of suitable groups to cause the complex to become located in a particular region or organ, such as the brain, of a mammal to which the complex is administered, will require no more than routine development work in the light of the common general knowledge in the field taken with the advice given in the specification. Complexes of isotopes of technetium other than Tc-99m are useful to determine the chemical properties of the complexes.
- n 2 or 3
- the groups R may be the same or different and each is hydrogen, hydrocarbon of 1 to 22 carbon atoms which may be alkyl, alkenyl, alkaryl, aralkyl or aryl, primary secondary or tertiary amine, primary, secondary or tertiary amide, carboxylic acid or carboxylic acid ester, hydroxyl or alkoxyl, or an acceptor-acid group, and may be substituted or unsubstituted.
- each R 1 , R and R 5 is hydrogen or C1 to C12 alkyl
- each of R 2 and R 3 is hydrogen, hydroxyl, C1 to C12 alkoxyl, C1 to C22 hydrocarbon which may be alkyl, alkenyl, alkaryl, aralkyl or aryl, or tertiary amine with 1 to 20 carbon atoms, or R 2 and R 3 may form, together with the carbon atom to which they are attached, a cycloaliphatic group which may be amine substituted.
- each of R 2 and R 3 is hydrogen or C1 to C4 alkyl.
- complexes preferred for brain imaging have partition coefficients between lipid and water and molecular weights such that in vivo they are capable of diffusing across the blood brain barrier and of being retained in the brain for a time sufficient to be used for diagnostic purposes.
- the invention also includes a method of body imaging which comprises administering to a mammal a complex of technetium-99m as defined above whereby the complex becomes localised in one or more regions of the mammal, and observing radiation emitted from the one or more regions.
- the invention also includes a method of forming a complex of technetium as defined above by the steps of a) complexing Tc-99m pertechnetate under reducing conditions with a complexing agent for technetium selected from alkylene amine oximes containing 2 or 3 carbon atoms in the alkylene group, which group is substituted or unsubstituted, any substituents present being of the kind useful for adapting radionuclide ligands for body imaging applications, and other weaker complexing agents for technetium, b) if another weaker complexing agent for technetium was used in step a), reacting the resulting complex with an alkylene amine oxime as defined in a) under conditions to promote ligand exchange, whereby there is formed the complex having a zero charge, containing an 0-H-0 ring closure bond, and being sufficiently stable for parenteral administration and imaging by scintillation scanning. group.
- a complexing agent for technetium selected from alkylene amine oximes containing 2
- the propylene amine oxime ligand starting material for preparing the complexes of this invention can be prepared by known synthetic procedures.
- PnAO as well as EnAO
- EnAO can be synthesized by the method of Vassian et al. Briefly described, this synthesis involves the reaction of 1,3-propanediamine (1,2-ethylenediamine) with the chloro-oxime reagent.
- chloro-oxime reagent has the general structure when R 4 , R 5 and R are alkyl.
- Such reagents can be prepared by reacting NOCl with the appropriate alkene as follows:- when R 4 and/or R 5 is hydrogen, another preparative route is preferred:-
- Propylene amine oxime or PnAO derivatives where substituent groups are introduced at the 2-carbon position of the propylene moiety can be prepared from diethylmalonate.
- a general scheme is outlined below for the synthesis by this route and involves the alkylation of the C-2 carbon followed by conversion of the diester functionalities to diamides with subsequent reduction to the 1,3-propane diamine derivative.
- Other routes from diester to diamine are possible, for example via the diol.
- the diamine product can then be reacted with the chloro-oxime reagent to form the respective PnAO derivative.
- analogue derivatives can be made by a similar reaction where 2-OH-diethylmalonate is reacted with RX.
- RX 2-OH-diethylmalonate
- the R group is attached to the C-2 propylene carbon by an ether linkage instead of directly to the C-2 propylene:
- the ester groups are converted to the amines and reacted with excess chloro-oxime to form the respective PnAO derivative.
- hydrophobic 1,3-propane diamine derivatives is to attach groups to the C1 and C3 carbon atoms of the propylene diamine. These derivatives can be made by reacting alpha-gamma- diketones (e.g., acetylacetone) with NH 3 , followed by reduction to produce the following 1-3-propane diamine derivatives and subsequent reaction with the chloro-oxime reagents.
- alpha-gamma- diketones e.g., acetylacetone
- the other principal starting material is the technetium-99m as pertechnetate (Tc04-99m).
- the pertechnetate reagent is freshly generated as the sterile, pyrogen free eluate from a standard molybdenum-99 (Mo-99): Tc-99m radionuclide generator.
- Mo-99 molybdenum-99
- Tc-99m radionuclide generator a standard molybdenum-99
- the T C 0 4 -99m is eluted from the column using aqueous physiological saline, such as isotonic (0.9M) NaCl.
- the eluate will contain a dilute solution of the pertechnetate, such as a molar concentration of about 10 - 6 - 10 - 9
- the complexation reaction between the propylene amine oxime ligand and the pertechnetate reagent may be carried out in an aqueous solution or a solvent mixture composed of isotonic saline and a water-miscible organic solvent under reducing conditions.
- Standard reducing agents can be employed, such as those that have been previously used in the reduction and ligand complexing of Tc-99m in commercial "kit-type" preparations.
- suitable reducing reagents include; SnCl 2 and other stannous salts, sodium dithionite, sodium borohydride, formamidine sulphuric acid,or Sn or Zr electrodes, etc.
- Tc-99m-PnAO can be prepared by a variety of reducing conditions (for example, we have prepared Tc-99m-PnAO by reducing Tc0 4 -99m in physiological saline at pH 8-10 in the presence of 0.004M PnAO with sodium dithionite), stannous salts are the most convenient method of preparation.
- the use of stannous salts is a particularly suitable means for providing the reducing agent in pre-formulated radiopharmaceutical "kits" for routine use in patients.
- the lyophilyzed contents of a sterile pyrogen free vial containing the stannous salt, complexing ligand and other chemical, possibly a buffer and stabilizing agent are combined with the eluate from a Mo-99-Tc-99m generator containing Tc0 -99m.
- the resulting Tc-99m chelate can then be injected into the blood stream of a patient.
- the complexes of this invention contain Tc-99m bound rather strongly, they can also be prepared by a process of ligand exchange. That is to say, the pertechnetate can be reduced initially in the presence of some different ligand that binds technetium relatively weakly. When the resulting Tc-99m-ligand complex is subsequently mixed with PnAO, the Tc-99m transfers to the PnAO and forms a complex according to this invention.
- the complexation reaction of Tc-99m with PnAO is not highly sensitive to pH as long as either high acid or basic conditions are avoided.
- the complexation reaction can be carried out at a pH of 5 to 10. In this pH range, complexation yields of greater than 95% are achieved by reducing Tc04-99m with stannous ion with excess PnAO in saline solution.
- the ligand concentration in saline at the time of Tc04-99m addition can be as low as 10- 5 M.
- the pH adjustment can be made with a variety of reagents, such as sodium bicarbonate, sodium acetate, sodium borate, or other salts suitable for buffering in this pH range.
- the temperature of the reaction is not critical, and may be carried out at room temperature. However, the rate of the reaction may be promoted, if desired, by using a temperature as high as 90°C.
- the desired complexing reaction occurs rapidly, and will usually be completed within 10 minutes. If desired, the completion of the reaction may be determined by a suitable test procedure, such as paper chromatography, electrophoresis, thin layer chromatography or high performance liquid chromatography (HPLC).
- a suitable test procedure such as paper chromatography, electrophoresis, thin layer chromatography or high performance liquid chromatography (HPLC).
- Tc-99m PnAO intravenous injection of Tc-99m PnAO in laboratory animals (i.e., mice, rats, rabbits, monkeys, and dogs) showed a high uptake by the brain and lung within a few seconds after injection. The activity in the brain decreases rapidly and becomes relatively low by 15 minutes. This uptake and washout of Tc-99m PnAO from the brains of dogs, rabbits, and rats was clearly visualized using a standard scintillation camera and interfaced directly to a computer. The images were digitized and processed by the computer.
- the activity expressed as a function of time of the Tc-99m-PnAO in the brain was evaluated by plotting the activity outlined by the region of interest (ROI) of the brain compared to an ROI over non-brain tissue against time.
- ROI region of interest
- the rate of Tc-99m PnAO washout in the dog was similar to that observed with clearance of Xe-133 from the brain in humans. This data indicates that the brain uptake of Tc-99m-PnAO is efficient and that measurement of washout iites of this-chelate from various areas of the brain with the proper instrumentation is, indeed, feasible.
- the specific SPECT instrumentation (1), multiprobe systems (2) currently used to follow the rate of Xe-133 brain clearance in humans can also be applied to determine regional clearance of Tc-99m-PnAO from the brain and determine rCBF patterns in patients. Even though less satisfactory, diagnostic information by planar imaging of the Tc-99m-PnAO uptake in the brain can also be obtained.
- Tc-99m-PnAO and various derivatives or other tetradentate amine oximes maintain the greatest potential of any known Tc-99m-chelates that could be used as a radiopharmaceutical to assess patterns of regional cerebral blood flow (rCBF) in humans.
- Tc-99m-PnAO could be used to assess rCBF using commercially available Nuclear Medicine instrumentation which has the capability of following the rate of washout of activity (e.g., Xe-133) from various regions of the brain.
- SPECT images can be obtained using a specialized Tomographic Unit (Tomomatic Model 64 Medimatic Corp, Irvine, CA) while the multiprobe system (Novo Cerebrograph marketed by Novo Laboratories, Inc., Wilton, CT) can be used to follow washout patterns_in localized brain areas.
- rCBF agent An alternative type of clinically useful rCBF agent is one that will passively diffuse across the intact BBB from the plasma and be retained intracellularly. The intracellular retention should be enough to permit imaging by conventional SPECT instrumentation.
- Tc-99m-PnAO chelates that will be useful for this purpose will in essence be designed to replace the I-123-phenyl substituent with the neutral-lipophilic Tc-99m-PnAo (or a PnAO analogue) substituent using the same or similar side chains attached as shown for Compounds A & B.
- the most straight forward methods to attach substituents to PnAO (or one of its analogues) is to attach the chain to the C-2 propylene by the diethylmalomate synthetic route described earlier.
- the substituent, attached either directly to or via an ether linkage to the C-2 propylene will be an alkyl amine or polyamine chain that may contain from 4-10 carbons.
- polyamine and alkyl amine chains that are attached to the phenyl ring in Compound A & B, respectively, are attached to PnAO (or a suitable analogue), they should produce a very desirable rCBF imaging agent.
- PnAO or a suitable analogue
- other alkyl amine and poly amine groups attached to PnAO may be superior.
- side chains see Winchell et al., (J.Nucl. Med., 20, 940-946, 1980).
- the PnAO analogue with a structure similar to Compound A can be prepared by reacting 2-(cyanoethyl)diethylmalonate with ammonia and subsequent reduction with sodium borohydride to form 2-(ethylamine)malondiamide.
- This compound can then be reated with C1CH 2 CH 2 CH 2 H(CH 3 ) 2 .HCl and then reduced with diborane to form the 1,3-propanediamine derivative.
- One part of this propane diamine derivative is then reacted with two parts of a chloro-oxime reagent to produce the desired.PnAO derivative.
- the second example involves reaction of the preformed Br-alkyl amine salt (i.e., BrCH 2 CH(CH 3 )NHCH(GH 3 ) 2 .HBr) with diethylmalonate followed by amidation, reduction with diborane and subsequent reaction of the 1,3-diamino propane derivative with a chloro-oxime reagent.
- the preformed Br-alkyl amine salt i.e., BrCH 2 CH(CH 3 )NHCH(GH 3 ) 2 .HBr
- Fatty acid analogues labelled with 1-123 have been shown to be effective for myocardial imaging in humans. Myocardial uptake and oxidative metabolism of these compounds is not critically dependent upon subtle structural differences. In fact, long chain fatty acid analogues that have bulky I-123-phenyl groups attached to the w-end by a variety of linking groups are taken up by heart muscle. For this reason, replacement of the I-123-phenyl substituent with Tc-99m-PnAO (or a Tc-99m PnAO analogue) should produce an agent with similar myocardial uptake because of the exceptional ease in which this neutral-hydrophobic chelate passes through biological membranes.
- Fatty acid analogues with PnAO attached to the w-end can be made using the diethyl malonate synthetic route outlined earlier.
- PnAO, or PnA0 analogues can be produced by reacting them with one of the chloro-oxime reagents.
- Tc-99m-PnAO-hexadecanoic acid is an analogue of w-I-123-phenyl-hexadecanoic acid which is known to localize in myocardial tissue. This general type of compound is taken up rapidly by heart muscle and clears because of beta-oxidation.
- an w-Tc-99m-PnAO derivative of a fatty acid with an alkyl substitution in the C-3 position should behave in vivo in a manner similar to the beta-methyl-w-I-123-phenyl fatty acid derivatives and find widespread applicability for metabolic imaging of the myocardium.
- one or two alkyl groups can be added to carbon atoms on the fatty acid chain other than at the beta-position which will cause metabolic trapping. To interrupt beta-oxidation, the alkyl groups must be on carbon atoms which are multiplets of 2 away from the beta-carbon.
- fatty acid analogues have limited solubility in aqueous solutions. Therefore, the feasibility of producing "kit” type formulations for routine human use demands that the Tc-99m-chelating group attached to the w-end of these analogues be able to form a stable chelate in high yields at low concentrations at or near neutral pH.
- the linear tetradentate amine oxime ligand e.g., PnAO
- PnAO linear tetradentate amine oxime ligand
- this type of ligand is the only one that will allow the production of a wide variety of Tc-99m-labelled fatty acid analogues with a stable-neutral-lipophilic chelate at the w-end by "kit"-type formulation.
- Tc-99m labelled compounds that are extracted from plasma by lung tissue may be useful in assessing various lung diseases.
- Tc-99m-PnAO has demonstrated significant lung tissue localization.
- Tc-99m-PnAO clears the blood and does not accumulate significantly in heart muscle
- the lung/blood and lung/heart ratios are both approximately 10/1 at 15 seconds post injection (these ratios are high enough to permit good lung imaging).
- All of the Tc-99m complexes of PnAO or its derivatives (PnAO analogues) that were outlined for use in brain images can also be used to assess lung disease.
- the alkyl derivatives (used to measure rCBF patterns by determining regional brain clearance) can be used to assess lung diseases where the uptake and washout of a neutral-lipophilic Tc-99m-Pharmaceutical is required (e.g. to determine differences in extravascular lung water).
- Tc-99m-PnAO, in its underivatized form should be suitable for these studies.
- the alkyl amine and polyamine derivatives proposed for brain imaging which are retained long enough for imaging with conventional SPECT instrumentation can also be used. These latter types of compounds would have lengthened lung retention (similar to Compound B because of their apparent binding to high-affinity amine binding sites located on the membranes of pulmonary endothelial cells.
- This type of Tc-99m compound could provide a method to routinely evaluate the metabolic function of the lung, especially the lungs effect on concentration of circulating bioamines.
- the tetradentate amine oxime ligand provides a unique opportunity to produce "kit"- type formulations of Tc-99m-labelled compounds for both brain and lung-imaging in clinical Nuclear Medicine.
- EnA0 will also form a neutral-lipophilic stable Tc-99m complex that passively diffuses across the intact BBB and other lipid-bilayer membranes. Accordingly, derivatized forms of EnAO with various substituents attached to the tetradentate ligand back bone, similar to the structures proposed for PnAO derivatization, can be synthesized. The only difference would be that substituents are attached to either one or both ethylene carbons instead of the propylene carbons in PnAO. These derivatives can be made by forming ethylene diamine derivatives as outlined below:- The ethylene diamine derivatives will react with a chloro-oxime reagent to form various substituted EnAO ligands.
- R 11 can be a fatty acid analogue side chain of 6 to 22 carbons linked by various groups (e.g. amides, ethers, etc.) with R 12 , R 13 , and R 14 being H atoms or one or more small (1-3 carbons) alkyl groups.
- R 11 and R 13 can be small alkyl side chains (1-5 carbons) with R 12 and R 14 equal to hydrogen (H) and formed using alpha-beta diketones.
- R 11 can be an alkyl or polyamine chain (with only secondary or tertiary amines).
- Tc-99m complexes of EnAO derivatives should have similar in vivo behaviour to the analogous Tc-99m-PnAO derivatives.
- PnA0 does not appear to be toxic. Swiss-Webster mice injected intravenously with approximately 1000-1500 times the anticipated mg/kg dose for humans showed no measurable or visible acute effects (see Example 21). This implies that these types of ligands, their derivatives and their Tc-99m-chelates will be safe to use in diagnostic Nuclear Medicine Procedures.
- Examples 1 to 17 describe preparation of EnAO, PnAO and derivatives of PnAO having the structure in which
- This compound was prepared from 1, 3-propane diamine and 2-chloro-2-methyl-3-nitrosopentane by the method described in Example 2. Yield 3.43g (46%).
- IR (KBr dis) 3300, 3190, 3050, 2990, 2060, 2930, 2870, 1650, 1460, 1390, 1380,1365, 1180, 1140, 1070, 1045, 1000, 950, 830, 780 and 650 cm -1 .
- NMR data are in ppm and IR data in cm 1 .
- the compound was prepared by reaction of 1,3-propanediamine and 2-chloro-2-methyl-3-nitrosoheptane by a method similar to that described in Example 2. Yield 60% m.pt. 170-172°C (dihydrochloride salt) 1 H NMR (free base, 200 MHz, CDCl 3 , ⁇ ppm) 0.96 (t,3H), 1.26 (s, 12H),1.20-1.70 (m, 12H), 2.27 (m, 4H), 2.45 (t,2H).
- This compound was synthesised from 1,3-propanediamine and 2-chloro-2-methyl-3-nitrosododecane by the method described in Example 2. Yield 37% m.pt. 185-186°C (dihydrochloride salt), 1 H NMR (free base, 60 MHz, CDC1 3 , ⁇ ppm); 2.55 (4H), 2.25 (m, 4H), 1.0-2.0 (m, 44H), 0.9 (dt,6H).
- This ligand was prepared in 41% yield by the reaction of 2,2-dimethyl-1,3-propanediamine and 2-chloro-2-methyl-3-nitrosobutane using the method described in Example 2. m.pt 151-2°C.
- the compound was prepared from 2-hydroxy-1,3-propanediamine and 2-chloro-2-methyl-3-nitrosobutane by the method described in Example 2. Yield 37%, m.pt. 139-40°C. 1 H NM R (60 M H z, DMSO-d 6 ⁇ ppm) ; 3.7 (m, 1H),.2.35 (m, 4H); 1.8 (s. 6H), 1.2 (s, 12H).
- diethylmorpholinylmalonate 24.50 g, 0.1 mol
- dry methanol 250 ml
- dry ammonia a catalytic amount of sodium (50 mg).
- the solution was re-saturated with ammonia and was left standing for 3 days.
- the resulting white crystals were filtered off and washed with methanol and ether and dried in vacuo.
- the ligand was prepared by reaction of 2 - morpholinylethyl-1,3-propanediamine and 2-chloro-2-methyl-3-nitrosobutane as described in Example 2. m.pt. 103-5°C.
- Examples 18 to 21 describe preparation and chemical properties of technetium complexes of EnAO, PnAO and PnA0 derivatives.
- Example 18 The complexes of Example 18 were subjected to test procedures which included high performance liquid chromatography (HPLC), ascending solvent paper chromatograph (PC), electrophoresis and solvent extraction. Crystal structure of solid Tc-PnAO was determined by x-ray diffraction.
- HPLC separations were done on a Hamilton PRP-1 column with a Beckman Series 332 dual pump gradient chromatograph system.
- the radioactivity in the eluent was detected by a NaI scintillation detector connected to a ratemeter.
- the signal from the ratemeter was directed to a Houston Instrument Co. Omniscribe B-5000 strip chart recorder and to a Hewlett-Packard Model 3390A integrator.
- the liquid phase at the beginning of separation was 0.02M NaH 2 P0 4 containing 2% CH 3 0H.
- THF was added at a gradient such that its volume % was 25 at 3.5 minuntes. Elution was continued at the concentration until 8.0 minutes, at which time the liquid phase was restored to 2% CH 3 0H to equilibrate the column for the next separation.
- Flow rate was 2 ml/min for all phases of the separation.
- Paper stips (5 x 120 mm cut from Gelman saturation pads) were spotted with 5 microlitres of sample 1 cm from the bottom of the strip and developed with acetone and with saline. The solvent front was allowed to ascend to the top of the strip.
- the strip was cut into six 2-cm sections and the Tc-99m in each determined by counting in a NaI well counter. Electrophoresis was carried out with a Gelman Deluxe Power Supply and Chamber using 0.1M NaHC0 3 buffer at pH 8.5 and Beekman #320046 electrophoresis strips at 300 volts for 45 or 60 minutes. The strips were scanned with a Technical Associates scanner or cut into sections as above.
- the percentage of pertechnetate and reduced Tc-99m can be determined from the activity in the electrophoresis anode peak and the saline paper chromatography origin section, respectively.
- a large electrophoresis peak at the origin in the absence of reduced Tc is evidence for a neutral complex.
- Tc-99m-PnAO complex prepared by one of the methods above was added to 5 ml of normal saline and the solution thoroughly mixed. One ml of this solution was added to 1 ml of n-octanol and vortexed for 1 minute and then centrifuged for 5 minutes. Ten-microlitre aliquots were withdrawn from each layer and counted in a NaI well scintillation counter. An 0.8-ml aliquot of the octanol layer was withdrawn and added to an equal volume of normal saline and the extraction and counting repeated as above. The results of this back extraction were used to compute the octanol/saline ratio. Similar experiments were done with CHC1 3 /saline as an approximate measure of complex yield. A high extractions ratio into these solvents indicates hydrophobity of the complex.
- the complex can be formed in high yield over the pH range 5.5. to 10 and is stable up to 24 hours at those same pH's. It was also found that complexes prepared at pH 8.5 and diluted by a factor of 1000 with normal saline were also stable for 24 hours.
- Structure of solid Tc-PnAO was determined by x-ray diffraction using data collected on an Enraf-Nonius CAD4 diffractometer. The structure solution was accomplished using the SDP program package of Enraf-Nonius on a PDP 11/34 computer and has been refined to a current agreement factor of 2.8%.
- the Tc is in the +5 oxidation state resulting in a net charge of zero for the ligand.
- the following general method was used to prepare Tc-99m complexes.
- the first step involves the preparation of a solution of the ligand within a pH range of 7.5 to 8.5. Both the physical form and the nature of the ligand will influence the preferred method for the preparation of the solution.
- solubility 2 to 3 mg of the ligand is dissolved in 0.5 ml of ethanol and 0.5 ml of 0.02M sodium bicarbonate solution in saline is added to adjust the pH to the required level.
- Determination of the distribution of radioactivity along each strip was conducted by means of a 100 channel analysis system interfaced to a Nova computer, programmed for peak integration.
- the Table, below, indicates the RF values of the major components of the Tc-99m solutions. With all ligands, the observed radiochemical purity of the Tc-99m complex was greater than 80%, and generally greater than 95%.
- HPLC analysis was conducted on a 150 x 4.1 mm stainless steel column packed with a divinylbenzene- styrene copolymer, reverse phase resin.
- the column was connected to a commercial dual pump gradient chromatographic system.
- the radioactivity in the eluent was detected by a NaI scintillation detector connected to a ratemeter. Output from the ratemeter was directed to a chart recorder and microcomputer programmed for peak integration.
- a flow of 100% solvent A was established at a flow rate of 2 ml/min prior to injection of a 10 microlitre sample.
- a linear solvent gradient was introduced, which increased the proportion of solvent B to 25% at six minutes post injection.
- the proportion of solvent B was maintained at 25% for a further 12 minutes; then reduced to 0% over 2 minutes.
- a flow of 100% solvent A at a flow rate of 2 ml/min was established prior to injection of a 10 microlitre sample.
- a linear solvent gradient was introduced which increased the proportion of solvent B to 75% over 13 minutes.
- the proportion of solvent B was maintained for a further 5 minutes, then reduced to 0% over 3 minutes.
- Tc-99m-Citrate was made by reducing 0.1 ml Tc-99m-pertechnetate in 1 ml 0.5 M citrate at pH 6.5 with 0.1 ml stannous tartrate (saturated aqueous solution). The % chelate formed was > 98%.
- Tc-99m-oxlate was made by reducing 0.1 ml Tc-99m-pertechnetate in 1 ml 0.5 M oxalate at pH 6.5 with 0.2 ml stannous tartrate (saturated aqueous solution).
- the % chelate formed was 85%. Less than 1% was in the pertechnetate form (determined using acetone solvent with paper chromatog) and 14.7% was Hydrolyzed-Red-Tc-99m (determined using saline as the eluant by paper chromatog).
- Examples 22 to 27 describe in vivo properties of the complexes prepared and characterized in the preceding Examples.
- Tc-99m complex solution 0.1 ml of the Tc-99m complex solution is administered by intravenous injection (lateral tail vein) to each of 5 rats (140-220 g). The injected dose is equivalent to approximately 200 ⁇ Ci of Tc-99m. Three rats are sacrificed at 2 minutes post injection, and two rats two hours post injection. At dissection the organs and tissue samples shown in the following Table are taken, and assayed for radioactivity. The uptake in each organ or tissue is calculated as a percentage of total activity recovered. Results are reported in Table 7. The Tc-99m EnAO demonstrates 0.85% i.d. uptake in rat brain at 15 seconds post injection.
- the apparatus consisted of a single gamma ray detector, fitted with a 1/8 inch single hole collimator, and connected to a multi-channel analyser operated on the multiscalar mode.
- the anaesthetised animal was position on the probe so that the brain was directly over the hole of the collimator.
- a bolus injection of Tc-99m PnAO was made into the internal carotid artery.
- the bolus was delivered in ⁇ 0.5 seconds through a 30 gauge needle, so as not to impede blood flow.
- the activity per 0:1 second counted by the detector was plotted as a function of time for ten minutes.
- the extraction efficiency determined by this method in rats, rabbits, and monkeys was observed in the range 70-90%.
- a blood sample is taken from the patient, and temperature, pulse rate, respiration rate and blood pressure are measured.
- the patient is placed in a supine position and a gamma camera positioned to obtain a vertex view.
- the gamma camera is connected to an image processing computer.
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Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US488184 | 1983-04-25 | ||
US06/488,184 US4615876A (en) | 1983-04-25 | 1983-04-25 | Macrocyclic complexes of technetium-99m for use as diagnostic radionuclides |
Publications (3)
Publication Number | Publication Date |
---|---|
EP0123504A2 true EP0123504A2 (de) | 1984-10-31 |
EP0123504A3 EP0123504A3 (en) | 1986-03-26 |
EP0123504B1 EP0123504B1 (de) | 1989-09-20 |
Family
ID=23938663
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP84302615A Expired EP0123504B1 (de) | 1983-04-25 | 1984-04-17 | Komplexe von Technetium-99m mit Alkylenaminoximen |
Country Status (11)
Country | Link |
---|---|
US (1) | US4615876A (de) |
EP (1) | EP0123504B1 (de) |
JP (2) | JPS6069090A (de) |
AU (1) | AU564636B2 (de) |
CA (1) | CA1231715A (de) |
CS (1) | CS271306B2 (de) |
DE (2) | DE123504T1 (de) |
DK (1) | DK173948B1 (de) |
ES (1) | ES8607977A1 (de) |
FI (1) | FI78706C (de) |
ZA (1) | ZA843069B (de) |
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EP0194843A2 (de) * | 1985-03-11 | 1986-09-17 | AMERSHAM INTERNATIONAL plc | Komplexe von Technetium-99m mit Propylen-Amin-Oximen |
EP0199260A2 (de) * | 1985-04-15 | 1986-10-29 | E.R. Squibb & Sons, Inc. | Boronsäureaddukte von Technetium-99M-Dioximkomplexen |
EP0229718A2 (de) * | 1986-01-16 | 1987-07-22 | AMERSHAM INTERNATIONAL plc | Markierung von Blutzellen |
EP0268801A1 (de) * | 1986-10-14 | 1988-06-01 | E.R. Squibb & Sons, Inc. | Technetium-99m-markierte Dioximkomplexe und für Markierung mit Technetium-99m geeignetes Präparat |
EP0277754A1 (de) * | 1987-01-30 | 1988-08-10 | AMERSHAM INTERNATIONAL plc | Verfahren unter Verwendung von Propylen Amin Oximkomplexen |
EP0279417A2 (de) | 1987-02-18 | 1988-08-24 | The Du Pont Merck Pharmaceutical Company | Durch Estergruppen substituierte Diamindithiole und davon abgeleitete radioaktiv markierte Komplexe |
WO1989001342A2 (en) * | 1987-08-07 | 1989-02-23 | Mallinckrodt, Inc. | Diagnostic or radiotherapeutic composition comprising a hydrogen containing compound |
US4818813A (en) * | 1984-10-24 | 1989-04-04 | Amersham International Plc. | Complexes of Technetium 99m with propylene amine oximes |
US4895960A (en) * | 1989-01-23 | 1990-01-23 | University Of Cincinnati | Cyclo substituted propyleneamine oxime and its use as a brain imaging agent |
EP0394126A1 (de) * | 1989-04-19 | 1990-10-24 | Medgenix Diagnostics | Verbindungen und Komplexe, besonders verwendbar für ärztliche Darstellung |
FR2646157A1 (fr) * | 1989-04-19 | 1990-10-26 | Ire Medgenix Sa | Ligands et complexes utiles notamment en imagerie medicale |
EP0417870A2 (de) * | 1989-09-11 | 1991-03-20 | INSTITUT FÜR DIAGNOSTIKFORSCHUNG GmbH AN DER FREIEN UNIVERSITÄT BERLIN | Chelatbildner zur Komplexierung von radioaktiven Isotopen, deren Metallkomplexe sowie ihre Verwendung in Diagnostik und Therapie |
US5026829A (en) * | 1989-01-23 | 1991-06-25 | University Of Cincinnati | Cyclo substituted propyleneamine oxime and its use as a brain imaging agent |
DE4017439A1 (de) * | 1990-05-30 | 1991-12-05 | Deutsches Krebsforsch | Polyethersubstituierte tumormittel |
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Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
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US20130195756A1 (en) | 2012-01-31 | 2013-08-01 | General Electric Company | 99mTc IMAGING AGENTS AND METHODS OF USE |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0038756A2 (de) * | 1980-04-18 | 1981-10-28 | Research Corporation | Kationische lipophile Komplexe von 99m Technetium, die für die myokardiale und hepatobiliäre Darstellung verwendbar sind |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4360511A (en) * | 1978-11-29 | 1982-11-23 | Medi-Physics, Inc. | Amines useful as brain imaging agents |
US4363793A (en) * | 1979-08-30 | 1982-12-14 | State University Of New York | Diagnostic radiopharmaceuticals for localization in target tissues exhibiting a regional pH shift relative to surrounding tissues |
US4352751A (en) * | 1979-09-10 | 1982-10-05 | Analytical Radiation Corporation | Species-linked diamine triacetic acids and their chelates |
-
1983
- 1983-04-25 US US06/488,184 patent/US4615876A/en not_active Expired - Lifetime
-
1984
- 1984-04-17 EP EP84302615A patent/EP0123504B1/de not_active Expired
- 1984-04-17 DE DE198484302615T patent/DE123504T1/de active Pending
- 1984-04-17 DE DE8484302615T patent/DE3479801D1/de not_active Expired
- 1984-04-19 AU AU27118/84A patent/AU564636B2/en not_active Expired
- 1984-04-24 CS CS843030A patent/CS271306B2/cs unknown
- 1984-04-24 ES ES531865A patent/ES8607977A1/es not_active Expired
- 1984-04-24 CA CA000452603A patent/CA1231715A/en not_active Expired
- 1984-04-24 DK DK198402052A patent/DK173948B1/da not_active IP Right Cessation
- 1984-04-25 ZA ZA843069A patent/ZA843069B/xx unknown
- 1984-04-25 FI FI841622A patent/FI78706C/fi not_active IP Right Cessation
- 1984-04-25 JP JP59083613A patent/JPS6069090A/ja active Granted
-
1989
- 1989-08-21 JP JP1214737A patent/JPH02160795A/ja active Granted
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0038756A2 (de) * | 1980-04-18 | 1981-10-28 | Research Corporation | Kationische lipophile Komplexe von 99m Technetium, die für die myokardiale und hepatobiliäre Darstellung verwendbar sind |
Non-Patent Citations (3)
Title |
---|
INORGANIC CHEMISTRY, vol. 12, no.11, 1973, pages 2631-2635; H. GOFF et al.: "Kinetic and thermodynamic studies on a labile trans-dinitrocobalt(III) complex" * |
THE JOURNAL OF NUCLEAR MEDICINE, vol. 20, no. 6, 1979, pages 641-642, New York, US; D.E. TROUTNER et al.: "Complexes of Tc-99m with cyclam" * |
THE JOURNAL OF NUCLEAR MEDICINE, vol. 24, no. 5, May 1983, page P10, New York, US; D.E. TROUTNER et al.: "A tetradentate amine oxime compoex of Tc-99m" * |
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US4818813A (en) * | 1984-10-24 | 1989-04-04 | Amersham International Plc. | Complexes of Technetium 99m with propylene amine oximes |
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EP0268801A1 (de) * | 1986-10-14 | 1988-06-01 | E.R. Squibb & Sons, Inc. | Technetium-99m-markierte Dioximkomplexe und für Markierung mit Technetium-99m geeignetes Präparat |
EP0277754A1 (de) * | 1987-01-30 | 1988-08-10 | AMERSHAM INTERNATIONAL plc | Verfahren unter Verwendung von Propylen Amin Oximkomplexen |
EP0279417A2 (de) | 1987-02-18 | 1988-08-24 | The Du Pont Merck Pharmaceutical Company | Durch Estergruppen substituierte Diamindithiole und davon abgeleitete radioaktiv markierte Komplexe |
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US5026829A (en) * | 1989-01-23 | 1991-06-25 | University Of Cincinnati | Cyclo substituted propyleneamine oxime and its use as a brain imaging agent |
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FR2646157A1 (fr) * | 1989-04-19 | 1990-10-26 | Ire Medgenix Sa | Ligands et complexes utiles notamment en imagerie medicale |
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WO1994008949A2 (en) * | 1992-10-08 | 1994-04-28 | Amersham International Plc | Metal-oxime chelates for use as radiopharmaceutical agents |
WO1994008949A3 (en) * | 1992-10-08 | 1994-06-09 | Amersham Int Plc | Metal-oxime chelates for use as radiopharmaceutical agents |
US5665329A (en) * | 1993-06-15 | 1997-09-09 | Bracco International B.V. | Heteroatom-bearing ligands and metal complexes thereof |
US5608110A (en) * | 1993-06-15 | 1997-03-04 | Bracco International B.V. | Heteroatom-bearing ligands and metal complexes thereof |
US5627286A (en) * | 1993-06-15 | 1997-05-06 | Bracco International B.V. | Heteroatom-bearing ligands and metal complexes thereof |
US5656254A (en) * | 1993-06-15 | 1997-08-12 | Bracco International B.V. | Polyaza heteroatom-bearing ligands and metal complexes thereof for imaging or radiotherapy |
US5741912A (en) * | 1993-06-15 | 1998-04-21 | Bracco International B.V. | Methods for preparing heteroatom-bearing ligands and metal complexes thereof |
WO1995004552A2 (en) * | 1993-08-04 | 1995-02-16 | Amersham International Plc | Radiometal complexes that localise in hypoxic tissue |
WO1995004552A3 (en) * | 1993-08-04 | 1995-03-23 | Amersham Int Plc | Radiometal complexes that localise in hypoxic tissue |
US5997843A (en) * | 1993-08-04 | 1999-12-07 | Amersham International Plc | Radiometal complexes that localise in hypoxic tissue |
US5663307A (en) * | 1994-01-12 | 1997-09-02 | Bracco International B.V. | Hydrazone containing ligands and metal complexes thereof |
US5651954A (en) * | 1994-01-12 | 1997-07-29 | Bracco International B.V. | Method of using hydrazone containing ligands and metal complexes thereof |
WO1995019338A1 (en) * | 1994-01-12 | 1995-07-20 | Bracco International B.V. | Ligands and metal complexes thereof |
US6660246B1 (en) | 1994-01-12 | 2003-12-09 | Bracco International, Bv | Ligands and metal complexes thereof |
WO2010118706A2 (es) | 2009-04-17 | 2010-10-21 | Centro De Neurociencias De Cuba | Procedimiento de obtención de nuevos derivados de naftaleno para el diagnóstico in vivo de la enfermedad de alzheimer |
EP2860169A2 (de) | 2009-04-17 | 2015-04-15 | Centro De Neurociencias De Cuba | Verfahren zum Erhalten von neuartigen Derivaten von Naphtalen für die In-vivo-Diagnose der Alzheimer-Krankheit |
US9764047B2 (en) | 2009-04-17 | 2017-09-19 | Centro De Neurociencias De Cuba | Method for obtaining novel derivatives of naphthalene for the in vivo diagnosis of alzheimer's disease |
Also Published As
Publication number | Publication date |
---|---|
FI841622A0 (fi) | 1984-04-25 |
US4615876A (en) | 1986-10-07 |
FI78706C (fi) | 1989-09-11 |
DK173948B1 (da) | 2002-03-04 |
DE3479801D1 (en) | 1989-10-26 |
DE123504T1 (de) | 1985-10-10 |
EP0123504B1 (de) | 1989-09-20 |
AU2711884A (en) | 1984-11-01 |
DK205284A (da) | 1984-10-26 |
CA1231715A (en) | 1988-01-19 |
CS303084A2 (en) | 1990-02-12 |
FI841622A (fi) | 1984-10-26 |
JPH0544931B2 (de) | 1993-07-07 |
FI78706B (fi) | 1989-05-31 |
EP0123504A3 (en) | 1986-03-26 |
ZA843069B (en) | 1984-11-28 |
CS271306B2 (en) | 1990-09-12 |
DK205284D0 (da) | 1984-04-24 |
JPH0211593B2 (de) | 1990-03-14 |
JPH02160795A (ja) | 1990-06-20 |
AU564636B2 (en) | 1987-08-20 |
JPS6069090A (ja) | 1985-04-19 |
ES8607977A1 (es) | 1986-06-01 |
ES531865A0 (es) | 1986-06-01 |
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